I. Intravenous Alcohol Self-Administration (IV-ASA) in humans Paradigms: We have conducted research to characterize IV alcohol self-administration (IV-ASA) across the spectrum of alcohol use and misuse. We initially developed a free-access (FA) paradigm where subjects could self-administer short standardized IV alcohol infusions via single button presses. We have demonstrated a high test-retest reliability of the paradigm, and shown that consumption measures obtained in the laboratory reflect recent drinking history, providing a degree of face validity to the paradigm. We also found robust positive relationships between IV-ASA and subjective feelings of drug effects, liking drug effects, intoxication, and stimulation. We have also developed a progressive ratio (PR) paradigm of IV-ASA to assess motivation for alcohol reward based on the principle that people will work harder for greater rewards. Results indicate robust test-retest reliability of the PR paradigm, and that PR-ASA measures were significantly associated with recent drinking history measures, and reflected subjective perceptions of alcohol hedonic and rewarding effects, including liking, high and intoxication. More recently, this paradigm was used in a collaborative study examining the effect of exogenous ghrelin on alcohol salience and consumption, and combined with standardized alcohol exposures to examine the relationship between subjective response and motivation to consume alcohol across the alcohol use spectrum. The PR paradigm represents a novel extension of IV-ASA methods, and will improve our understanding of what drives alcohol seeking and consumption behavior. It also offers an attractive translational biomarker in evaluation of experimental therapeutics for AUD. Modeling Binge Consumption: The IV-ASA model provides the ability to characterize the magnitude and duration, but also the rate and trajectory of an individuals preferred alcohol exposure during the session. This feature enables the ability to assess binge consumption, i.e., consuming alcohol to BrACs exceeding 0.08%, under highly controlled conditions. Binge drinking is associated with a greater risk of negative acute and chronic adverse consequences, and has a major impact on psychological and physical well-being. Data from our IV-ASA studies indicated that approximately 38% of our participants achieved binge-level exposures during the session. Using time-to-event analysis, we showed that faster rates of alcohol consumption to binge-levels were associated additively with risk factors for AUD, including family history of alcoholism, male sex, impulsivity, and low level of response to alcohol. These recently published results indicate that faster binge drinking in non-dependent drinkers may be an early indicator of vulnerability to AUD and should be carefully assessed as part of a thorough clinical evaluation. Additional analyses have extended these findings across the spectrum of drinking, demonstrating that social drinkers with high-risk factors for AUD achieve rates of binge consumption akin to heavy drinkers. The utility of the IV-ASA paradigm in modeling binge-consumption behavior could provide additional insights into the biobehavioral mechanisms and sources of inter-individual variability in this compulsive aspect across the spectrum of use and misuse. Understanding neurobiological domains underlying AUD: IV-ASA paradigms can have great utility in characterizing the pharmacodynamics of alcohol across neurobiological domains that are relevant to addiction. Alcohol response phenotypes span a wide and heterogeneous range from subjective effects on mood and behavior to objective functional impairment to physiological effects. These response measures can be broadly categorized into domains including: (1) Reward/Incentive Salience, which may include effects such as stimulation, liking, wanting, craving, (2) Negative Valence, which may include subjective and psychophysiological reactivity to stress cues, and (3) Executive Control, which includes effects such as loss of control and ability to resist, as well as impulsivity and compulsivity. These domains are consistent and aligned with the recently proposed alcohol neuroclinical assessment (ANA) domains within the alcohol addiction framework, and map onto the 3 stages of the so-called Koobian cycle of addiction: binge-intoxication, preoccupation-anticipation, and withdrawal-negative affect. Our work suggests that the free-access and progressive-ratio IV-ASA paradigms primarily assesses alcohol seeking and consumption driven by the incentive salience and reinforcing properties of alcohol, and can therefore be useful in assessing the underpinnings of alcohol reward. Also, as described above, the IV-ASA paradigm can be used to examine binge consumption which may reflect reward and compulsive use. We have recently completed a study combining IV-ASA with acute stress cue exposure to characterize the phenotype of stress-induced craving and consumption of alcohol. In addition, we are currently developing a human laboratory model of impaired control over alcohol consumption. These human lab models provide a unique opportunity to provide a deeper understanding of the alcohol-response phenotypes across the spectrum of alcohol use and problems, and to determine the sources of individual variation in these response phenotypes. Given the critical and essential relationship between alcohol response and risk for AUD, this approach can provide novel and important insights into the etiology of AUD as well as support the development of novel pharmacological targets for treatment of AUD. II. Human Laboratory Models in Medication Development for Alcoholism The Section is developing and utilizing human laboratory models to examine the effects of pharmacological agents for the treatment of alcohol use disorder (AUD). These translational studies can complement preclinical studies to screen novel therapeutics that are likely to succeed in clinical trials, thus facilitating future medication development for AUD. The first experimental medicine conducted by the Section examined the effect of varenicline, a (nicotinic) acetylcholine receptor partial agonist approved for smoking cessation, in non-treatment seeking heavy drinkers. This study was reported in previous annual reports and indicated that medication repurposing of varenicline could be targeted towards reward-drinking individuals seeking help for treatment of AUD. This study also demonstrates the utility of human laboratory paradigms and the use of fMRI-derived brain biomarkers in medications development for AUD. Currently, the Section is conducting a study examining the effect of opioid receptor modulation using nalmefene on IV-ASA and neural response to alcohol cues, and the moderating role of OPRM1 gene variation on these effects, in heavy drinkers. This study could provide important information about the underlying mechanisms of opioid receptor modulation in alcohol response, and could provide novel data to enable treatment providers to develop personalized medicine approaches to increase the likelihood of therapeutic benefit of nalmefene and other opioid antagonists in the treatment of AUD. III. Collaborative Studies: 1) Sleep disturbance and relapse in individuals with alcohol dependence: An exploratory mixed methods study (PI: Gwenyth Wallen, NIH CC). 2) The neurophysiological effects of intravenous alcohol as potential biomarkers of ketamine's rapid antidepressant effects in major depressive disorder (PI: Carlos, Zarate, NIMH). 3) Using the alcohol clamp to examine the mechanistic relationship between ethanol and atrial fibrillation (PI: Greg Marcus, UCSF) 4) Translational imaging genetics project to examine the role of nicotine receptor gene variation and alcohol reward (Co-PI: Mariella De Biasi